The present invention relates to an optically active epoxypropionate derivative, an intermediate thereof and processes for their production. The optically active propionate derivative of the present invention is useful as an intermediate for the preparation of pharmaceuticals or agricultural chemicals.
As an optically active propionate derivative, one having a methoxy group introduced at the 4-position (the p-position) of a phenyl ring, is known as an intermediate for the preparation of a known diltiazem (see, for example, JP-A-60-13776 and JP-A-6-287183). However, an optical active epoxypropionate derivative of the following Formula (1): 
wherein symbol * represents optically active carbon, or the following Formula (2): 
wherein symbol * represents optically active carbon, has not been known.
Further, as a process for producing an optically active epoxypropionate derivative, a process for separating an optically active substance from a racemic modification by optical resolution is known, but a process for producing such a compound by an asymmetric synthesis has not been known.
Under these circumstances, the present invention has been made, and it is an object of the present invention to provide a novel optically active epoxypropionate derivative expected to be an intermediate for the preparation of pharmaceuticals or agricultural chemicals, an intermediate for its preparation and a process for their production.
The present inventors have conducted an extensive study to prepare a novel optically active epoxypropionate derivative expected to be an intermediate for the preparation of pharmaceuticals or agricultural chemicals and as a result, have found the optically active epoxypropionate derivative of the above Formula (1) or (2) and an optically active epoxyenone derivative of the following Formula (3): 
wherein symbol * represents optically active carbon, which is an intermediate for the preparation of the compound of the above formula (1). And, they have found processes for their production by asymmetric syntheses. The present invention has been accomplished on the basis of these discoveries.
Namely, the present invention provides the optically active epoxypropionate derivative of the above Formula (1) or (2), the optically active epoxyenone derivative of the above Formula (3) and processes for their production.
Now, the present invention will be described in detail with reference to the preferred embodiments.
The optically active epoxypropionate derivative of the above Formula (1) of the present invention is specifically t-butyl(2S, 3R)-trans-2,3-epoxy-3-(4xe2x80x2-fluorophenyl) propionate, t-butyl(2S, 3R)-trans-2,3-epoxy-3-(3xe2x80x2-fluorophenyl) propionate, t-butyl(2S, 3R)-trans-2,3-epoxy-3-(2xe2x80x2-fluorophenyl) propionate, t-butyl(2R, 3S)-trans-2,3-epoxy-3-(4xe2x80x2-fluorophenyl) propionate, t-butyl(2R, 3S)-trans-2,3-epoxy-3-(3xe2x80x2-fluorophenyl) propionate, or t-butyl(2R, 3S)-trans-2,3-epoxy-3-(2xe2x80x2-fluorophenyl) propionate.
The optically active epoxypropionate derivative of the above Formula (2) of the present invention is specifically phenyl trans-3-(2-chlorophenyl)-(2S, 3R)-epoxypropionate, phenyl trans-3-(3-chorophenyl)-(2S, 3R)-epoxypropionate, phenyl trans-3-(4-chlorophenyl)- (2S, 3R)-epoxypropionate, phenyl trans-3-(2-chlorophenyl)-(2R, 3S)-epoxypropionate, phenyl trans-3-(3-chlorophenyl)-(2R, 3S)-epoxypropionate, or phenyl trans-3-(4-chlorophenyl)-(2R, 3S)-epoxypropionate.
The optically active epoxyenone derivative of the above Formula (3) of the present invention is specifically (1R, 2S)-trans-1,2-epoxy-1-(4xe2x80x2-fluorophenyl)-4,4-dimethyl-pentan-3-one, (1R, 2S)-trans-1,2-epoxy-1-(3xe2x80x2-fluorophenyl)-4,4-dimethyl-pentan-3-one, (1R, 2S)-trans-1,2-epoxy-1-(2xe2x80x2-fluorophenyl)-4,4-dimethyl-pentan-3-one, (1S, 2R)-trans-1,2-epoxy-1-(4xe2x80x2-fluorophenyl)-4,4-dimethyl-pentan-3-one, (1S, 2R)-trans-1,2-epoxy-1-(3xe2x80x2-fluorophenyl)-4,4-dimethyl-pentan-3-one, or (1S, 2R)-trans-1,2-epoxy-1-(2xe2x80x2-fluorophenyl)-4,4-dimethyl-pentan-3-one.
The compound of the above Formula (1) of the present invention can be prepared by the following synthetic route using a known enone as the staring material, although the preparation is not particularly limited. 
In the above formulae, symbol * represents optically active carbon.
Namely, the optically active epoxyenone derivative of the above Formula (3) is prepared by asymmetric epoxidation of an enone, and further, the derivative is oxidized with an oxidizing agent, whereby the optically active epoxypropionate derivative of the above Formula (1) is prepared.
Further, the compound of the above Formula (2) of the present invention can be prepared by the following route by asymmetric epoxidation of an enone using a known enone as the starting material, although the preparation is not particularly limited. 
In the formulae, symbol * represents optically active carbon.
As a catalyst to be used for the asymmetric epoxidation reaction of the present invention, any asymmetric epoxidation catalyst for enones can be used. However, it is preferred to employ a catalyst comprising:
(A) an optically active binaphthol,
(B) lanthanum triisopropoxide,
(C) triphenylphosphine oxide, and
(D) cumene hydroperoxide (hereinafter referred to as CMHP) or tert-butyl hydroperoxide (hereinafter referred to as TBHP), since the substrate selectivity is low, and it provides good yield and a high optical purity. Here, in the present invention, the optically active binaphthol is specifically (R)-(+)-1,1xe2x80x2-bi-2-naphthol (hereinafter referred to as (R)-binaphthol) or (S)-(xe2x88x92)-1,1xe2x80x2-bi-2-naphthol (hereinafter referred to as (S)-binaphthol).
With respect to the constituting proportions of the above-mentioned catalyst components, theoretically, the respective constituting components may be present in equivalent amounts. However, in order to let the catalyst form stably in the reaction system, (A) the binaphthol is usually from 1 to 3 mols, preferably from 1 to 1.5 mols, (C) the triphenylphosphine oxide is usually from 0.1 to 10 mols, preferably from 1 to 10 mols, and (D) CMHP or TBHP is usually from 1 to 20 mols, preferably from 1 to 10 mols, per mol of (B) the lanthanum triisopropoxide.
In the asymmetric epoxidation reaction of the present invention, it is preferred that the above catalyst components are preliminarily formulated into a catalyst solution in the reaction system and then used for the epoxidation reaction of an enone.
Further, in the asymmetric epoxidation reaction of the present invention, if (R)-binaphthol is employed, the steric configuration at the 2-position (xcex1-position of carbonyl group) and 3-position (xcex2-position of carbonyl group) of the epoxyenone of the present invention will be (2S, 3R), and if (S)-binaphthol is employed, it will be (2R, 3S).
In the asymmetric epoxidation reaction of the present invention, the amount of the catalyst is not particularly limited, but it is usually within a range of from 0.01 to 50 mol %, more preferably within a range of from 0.1 to 25 mol %, based on the molar amount of the lanthanum isopropoxide, relative to the substrate subjected to the reaction.
The solvent useful for the asymmetric epoxidation reaction of the present invention may be any solvent so long as it is a solvent inert to the catalyst and to the epoxidation reaction. However, from the viewpoint of the stability of the catalyst and the reaction efficiency of the epoxidation reaction, an ether type solvent such as dimethyl ether, diisopropyl ether, 1,2-dimethoxyethane or tetrahydrofuran (hereinafter referred to as THF), is preferred, and among them, it is THF that gives the highest results. Such a solvent can be used also as a solvent for the preparation of the above catalyst solution.
The amount of the solvent is usually from 2 to 200 times, preferably from 5 to 100 times, by weight, to the enone to be subjected to the reaction.
In the asymmetric epoxidation reaction of the present invention, a complex catalyst comprising:
(A) an optically active binaphthol,
(B) lanthanum triisopropoxide,
(C) triphenylphosphine oxide, and
(D) cumene hydroperoxide or tert-butyl hydroperoxide, presents a higher optical activity to the product.
In the preparation of the complex catalyst, the time for formation of the catalyst varies depending upon the proportions of the components constituting the catalyst, selection of the oxidizing agent, the type of the solvent and the concentration of the catalyst. However, the complex catalyst can be formed usually by maintaining the mixture for from 0.5 to 4 hours within a range of from xe2x88x9250xc2x0 C. to 100xc2x0 C., and the solution after the formation of the complex shows a color of yellowish green to deep green.
As TBHP to be used as an oxidizing agent in the asymmetric epoxidation reaction of the present invention, a commercially available solution in e.g. decane may be used as it is, or it may be extracted by toluene from a 70% or 90% aqueous solution, followed by drying over e.g. magnesium sulfate, and then may be used in the present invention. Further, as CMHP, a commercially available 80 wt % product may be used after purification or as it is without purification. Preferably, purified or commercially available CMHP is employed, whereby a pure optically active substance can be obtained.
For the asymmetric epoxidation reaction of the present invention, the above enone is added to the preliminarily prepared catalyst solution, and then CMHP or TBHP is supplied to carry out the reaction. With respect to the supply rate of the oxidizing agent, the supply is carried out under such a condition that the oxidizing agent will not be in large excess in the system. Specifically, the supply rate is determined by measuring the reaction rate in the actual system, whereupon the supply is carried out. If the supply rate is higher than the reaction rate, the yield may decrease, and if it is lower, the optical purity may decrease.
In the asymmetric epoxidation reaction of the present invention, the amount of the oxidizing agent should theoretically be sufficient with an equivalent amount to the enone subjected to the reaction, as the sum of the amount used for forming the catalyst and the amount added during the reaction. However, in order to complete the reaction, it is preferably used in an amount of at least 1.1 times by mol.
The reaction temperature in the asymmetric epoxidation reaction of the present invention varies depending upon the difference in the substrate of the enone, but it is usually within a range of from xe2x88x9250xc2x0 C. to 100xc2x0 C. With respect to the reaction time, the reaction is completed usually within 48 hours.
In the asymmetric epoxidation reaction of the present invention, zeolite may be used, as the case requires, for the purpose of removing water in the system during the preparation of the catalyst and during the reaction or for the purpose of accelerating the catalyst-forming reaction or the epoxidation reaction. The zeolite may be used in any ratio to the enone, but it is used usually in an amount of from about 10 mg to 2 g per mmol of the enone. With respect to the type of the zeolite, various zeolites can be used including type A zeolites represented by molecular sieves 3A, 4A, and 5A, molecular sieve 13X, type Y zeolite and type L zeolite. Among these, molecular sieve 4A is preferred.
After completion of the epoxidation reaction of the present invention, post treatment for purification by e.g. column chromatography is carried out, whereby the optically active epoxyenone of the above Formula (3) or (4) can be obtained in good yield with a high optical purity.
The process of obtaining the optically active epoxypropionate of the present invention is not particularly limited. For example, the optically active epoxyenone obtained by the above method is oxidized by a Baeyer-Villiger reaction to obtain the desired product.
As the oxidizing agent to be used for the Baeyer-Villiger reaction of the present invention, any peracid or peroxide may be employed. However, specifically, potassium persulfate, hydrogen peroxide, perbenzoic acid, m-chloroperbenzoic acid, CMHP or TBHP may, for example, be mentioned. The reaction is carried out usually within a temperature range of from 0xc2x0 C. to 150xc2x0 C. for from 1 to 48 hours to obtain the desired product. Further, depending upon the type of the peracid or peroxide, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide may be used in combination, and the reaction may be carried out in a water/alcohol solvent.
The amount of the oxidizing agent to be used in the Baeyer-Villiger reaction of the present invention is usually from 1 to 10 times by mol, preferably from 2 to 5 times by mol, relative to the epoxyenone subjected to the reaction.
After completion of the Baeyer-Villiger reaction of the present invention, the peracid or peroxide is deactivated, and then, the optically active epoxypropionate derivative as the desired product, can be obtained by extraction with an organic solvent, followed by drying, concentration and purification by column chromatography.
The optically active epoxypropionate derivative of the present invention has a high optical purity and is expected to be an important intermediate for various pharmaceuticals or agricultural chemicals.
Now, the present invention will be described in further detail with reference to Examples. However, it should be understood that the present invention is by no means restricted to such specific Examples.
Further, for the analyses of the products, the following equipments were employed.
Measurement of optical rotation
SEPA-300, manufactured by HORIBA K. K. was used.
Measurement of melting point
MP-500D manufactured by Yanako K. K. was used.
Measurements of 1H-NMR and 13C-NMR
Gemini-200, manufactured by Varian, was used (200 MHz).
Measurement of MASS
M-80B, manufactured by Hitachi, was used.
Measurement of IR
200OFT-IR, manufactured by Perkin Elmer, was used.
Determination of optical purity
High performance liquid chromatography having chiral column AD of Daicel K. K. mounted, was used, and the measurement was carried out at a flow rate of 1 ml/min with an eluent of hexane/i-PrOH=95/5 (vol/vol).